A new concise synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives

Article abstract of DOI:10.1039/c3nj00618b

A new T3P-assisted, convenient and efficient procedure for the synthesis of dihydroquinazolinones is described. The main advantages of this protocol include its practical simplicity, short reaction times and particularly the ease with which products are isolated.

Full text of DOI:10.1039/c3nj00618b

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A new concise synthesis of 2,3-dihydroquinazolin-
4
(1H)-one derivatives†
Cite this: NewJ.Chem., 2013,
3
7, 3595
Matthieu Desroses,* Martin Scobie and Thomas Helleday
Received (in Montpellier, France)
1
0th June 2013,
Accepted 23rd August 2013
DOI: 10.1039/c3nj00618b
www.rsc.org/njc
s
A new T3P -assisted, convenient and efficient procedure for the
synthesis of dihydroquinazolinones is described. The main advan-
tages of this protocol include its practical simplicity, short reaction
times and particularly the ease with which products are isolated.
Table 1 Optimization of the reaction conditions
The quinazolinone ring is observed in several important natural
and synthetic organic derivatives. It has also been established as Entry
s
T3P (equiv.)
a
Time (min)
Conversion (%)
a useful privileged scaffold for library design and drug discovery
1
1
0
1
1
1
0.5
0.25
30
30
20
10
5
10
10
100
2
99
98
92
95
92
1
applications. Many 2,3-dihydroquinazolinones are reported to
be interesting as anticancer, antibiotic, analgesic, antihistaminic
2
3
4
5
6
7
2
and antidepressant agents. Consequently, a number of synthetic
methods have been reported for their synthesis. In particular,
synthetic routes based on cyclisation of simple aminobenzamide
3
4
a
derivatives with aldehydes employing amberlyst-15, b-cyclodextrin,
Determination by LC/MS at 254 nm.
5
6
ionic liquids, ammonium chloride, Br o¨ nsted and phosphoric
7,8
9
10
4
acids, tetrabutyl ammonium bromide, TiCl /Zn and cerium(IV)
s
In the presence of one equivalent of T3P (50% solution
1
1
ammonium nitrate (CAN) have been used for this purpose.
However, these methods suffer from lengthy procedures and/or
low yields.
in EtOAc), a clean and complete reaction occurred at room
temperature within 30 minutes (Table 1, entry 1).
s
To clarify the role of T3P in this process, the same reaction
We have already described the highly effective use of propyl-
s
s
was conducted without T3P (Table 1, entry 2). Only a small
phosphonic anhydride (T3P ) in the Fischer indole synthesis,
amount of the expected compound (e.g. 2%) was observed after
the Pictet–Spengler reaction and in the synthesis of diverse
1
2
3
0 minutes of reaction. We then explored the influence of the
pyrazolones. In continuation of our investigations, we report
here the efficient and rapid synthesis of 2,3-dihydroquinazolinones
s
reaction time and the stoichiometry of T3P on the reaction
rate. A good conversion of 98% was obtained within 10 minutes
using one equivalent of T3P while 92% of conversion was
s
catalyzed by T3P .
s
Acetonitrile has been found to be one of the most effective
1
3
obtained even with a shorter reaction time of 5 minutes (Table 1,
solvent mediums for the generation of dihydroquinazolinones.
s
entries 4 and 5). Decreasing the number of equivalents of T3P to
In a model reaction between 2-aminobenzamide (1a, 0.5 mmol)
and benzaldehyde (2a, 0.5 mmol) in acetonitrile, we investigated
the synthesis of dihydroquinazolinone 3a.
0
1
9
.5 and 0.25 equivalents, respectively, and using a reaction time of
0 minutes led to reduced conversion (entries 6 and 7, 95% and
s
2%, respectively), confirming the catalytic role of T3P .
Encouraged by this success, we studied this reaction with
Science for Life Laboratory, Unit of Translational Medicine and Chemical Biology,
Department of Medical Biochemistry and Biophysics, Karolinska Institute,
S-171 21 Stockholm, Sweden. E-mail: matthieu.desroses@scilifelab.se
a range of other aldehydes 2 using optimized conditions
s
(
T3P 1 equiv., 10 minutes at room temperature in acetonitrile),
furnishing the respective dihydroquinazolin-4(1H)-ones 4 in
good yields. The results are summarized in Table 2.
†
Electronic supplementary information (ESI) available: Experimental details and
1
13
H and C NMR spectra of all the compounds. See DOI: 10.1039/c3nj00618b
This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem., 2013, 37, 3595--3597 3595

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Table 2 Aldehyde scope of the reaction
Table 2 (continued )
Yield (%) Entry
Aldehyde
a
a
Entry
Aldehyde
Product
Time (min)
10
Product
Time (min)
Yield (%)
1
92
90
89
85
91
93
16
15
15
85
1
7
86
2
3
4
5
6
10
10
10
10
10
a
Reactions conducted on a 0.5 mmol scale, isolated yield.
To our delight, this process was applicable to diverse substrates.
Aromatic aldehydes with electron-donating or -withdrawing sub-
stituents reacted very well, affording good to excellent yields of
2
,3-dihydroquinazolinones (Table 2, entries 1 to 11). No significant
differences in the yields were observed, indicating that the nature
or the position of the substituent had negligible influence on the
rate of the reaction. Similarly, heterocyclic aldehydes gave the
expected products in excellent yields (entries 12–13).
Finally, we were also pleased to see that, even though a
slightly longer reaction time was needed (15 minutes), linear or
cyclic aliphatic aldehydes produced the desired compounds in
good yields (Table 2, entries 15–17). The dihydroquinazolinones
were generally precipitated from the reaction mixtures and simple
filtration and washing with a little acetonitrile afforded the
expected products in sufficient purity.
7
10
88
In conclusion, a simple and efficient protocol has been
developed for the synthesis of 2,3-dihydroquinazolinones which
are a key feature in numerous natural and synthetic therapeutic
compounds. Most of the reported methods to prepare these
8
9
10
10
92
87
4
–8
heterocycles suffer from a longer reaction time,
a tedious
11
9,10
procedure and/or drastic conditions. This method, employing
s
T3P as the catalyst, has several advantages such as a simple
operational procedure, a short reaction time (10–15 minutes),
the use of very mild conditions (room temperature) and an easy
access to the compounds in good to excellent yields.
The synthesis of other important heterocycles by using T3P
is under investigation in our laboratory.
1
1
1
1
1
0
1
2
3
4
10
10
10
10
10
89
90
93
94
87
s
Experimental section
1
4
14
14
15
16
17
14
3
16
Compounds 3a, 3b, 3c, 3d, 3g, 3h, 3i, 3j, 3k,
1
4
18
14
14
3n, 3o, 3p and 3q are all known compounds; spectral
data obtained were in agreement with the proposed structures
and matched those reported in the literature.
Melting points were obtained using a Stuart Scientific SMP3
apparatus and are uncorrected.
2-(2-Methylphenyl)-2,3-dihydroquinazolin-4(1H)-one (3e)
s
T3P (50% in EtOAc) (1 equiv., 0.5 mmol) was added to a
solution of 2-aminobenzamide (1a, 0.5 mmol) and 2-methyl-
benzaldehyde (2e, 0.5 mmol) in acetonitrile (1 mL) in a sealed
tube. After completion of the reaction (10 min, indicated by
1
5
15
89
2 2
TLC, eluent CH Cl –MeOH 95/5), the reaction mixture was
3
596 New J. Chem., 2013, 37, 3595--3597
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purified by column chromatography on a silica gel on a Biotage Acknowledgements
2 2
SP4 apparatus, gradient CH Cl –MeOH 1 to 10%.
Technical support from The Laboratories for Chemical Biology
at Karolinska Institutet (LCBKI) (http://www.cbcs.se/lcbki/) and
ChemAxon (http://www.chemaxon.com) is gratefully acknowledged.
Yield: 108 mg (91% yield, white powder), m.p. (EtOH)
1
88–189 1C.
1
H NMR (400 MHz, DMSO-d ) d (ppm): 8.05 (br s, 1H), 7.66
6
(
6
(
d, 1H, J = 7.6 Hz), 7.57 (dd, 1H, J = 7.6 Hz), 7.30–7.21 (m, 4H),
.86 (br s, 1H), 6.76 (d, 1H, J = 7.6 Hz), 6.72–6.68 (m, 1H), 6.00
s, 1H), 2.43 (s, 3H).
Notes and references
1
3
C NMR (100 MHz, DMSO-d
6
) d (ppm): 164.0, 148.5, 138.0,
1 M. E. Welsch, S. A. Snyder and B. R. Stockwell, Curr. Opin.
Chem. Biol., 2010, 14, 347.
2 M. Narasimhulu and Y. R. Lee, Tetrahedron, 2011, 67, 9627
and references therein.
3 P. VNS Murthy, D. Rambabu, G. Rama Krishna, C. Malla
Reddy, K. R. S. Prasad, M. V. Basaveswara Rao and M. Pal,
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Y. V. D. Nageswar, Tetrahedron Lett., 2012, 53, 6936.
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9, 972.
1
4
36.0, 133.1, 130.6, 128.4, 127.4, 125.9, 117.1, 114.8, 114.4, 64.6,
8.5, 18.7.
+
LCMS [M + H] m/z 239.
s
Typical procedure. T3P (50% in EtOAc) (1 equiv., 0.5 mmol)
was added to a solution of 2-aminobenzamide (1a, 0.5 mmol)
and aldehyde (0.5 mmol) in acetonitrile (1 mL) in a sealed tube.
After completion of the reaction (indicated by TLC, eluent
2 2
CH Cl –MeOH 95/5), the precipitate formed was filtered,
washed with cold acetonitrile (2 Â 1 mL) and dried to afford
the expected compound in sufficient purity.
6
A. Shaabani, A. Maleki and H. Mofakham, Synth. Commun.,
008, 38, 3751.
2-(4-Oxo-1,2,3,4-tetrahydroquinazolin-2-yl)benzonitrile (3f)
2
Yield: 116 mg (93% yield, white solid), m.p. (EtOH) 178–180 1C.
7 M. Rueping, A. P. Antonchick, E. Sugiono and K. Grenader,
Angew. Chem., Int. Ed., 2009, 48, 908.
1
H NMR (400 MHz, DMSO-d ) d (ppm): 8.30 (br s, 1H), 7.92
6
(
1
6
d, 1H, J = 7.6 Hz), 7.80–7.75 (m, 2H), 7.68 (dd, 1H, J = 7.6 Hz,
8 X. Cheng, S. Vellalath, R. Goddard and B. List, J. Am.
Chem. Soc., 2008, 130, 15786.
9 A. Davoodnia, S. Allameh, A. R. Fakhari and N. Tavakoli-
Hoseini, Chin. Chem. Lett., 2010, 21, 550.
.3 Hz), 7.63–7.59 (m, 1H), 7.31 (t, 1H, J = 7.6 Hz), 7.11 (br s, 1H),
.77–6.72 (m, 2H), 6.07 (d, 1H, J = 2.3 Hz).
1
3
6
C NMR (100 MHz, DMSO-d ) d (ppm): 163.3, 147.7, 143.3,
1
1
33.4, 133.3, 129.8, 128.6, 127.3, 117.7, 117.1, 114.6, 114.5, 10 D. Shi, L. Rong, J. Wang, Q. Zhuang, X. Wang and H. Hu,
10.9, 66.1.
LCMS [M + H] m/z 250.
Tetrahedron Lett., 2003, 44, 3199.
11 M. Wang, J. J. Gao, Z. G. Song and L. Wang, Chem. Heterocycl.
Compd., 2011, 47, 851.
+
2
-(Thiophen-3-yl)-2,3-dihydroquinazolin-4(1H)-one (3l)
1
2 (a) M. Desroses, K. Wieckowski, M. Stevens and L. R. Odell,
Tetrahedron Lett., 2011, 52, 4417; (b) M. Desroses,
T. Koolmeister, S. Jacques, S. Llona-Minguez, M. C.
Jacques-Cordonnier, A. C ´a zares-K o¨ rner, T. Helleday and
M. Scobie, Tetrahedron Lett., 2013, 54, 3554; (c) M. Desroses,
M. C. Jacques-Cordonnier, S. Llona-Minguez, S. Jacques,
T. Koolmeister, T. Helleday and M. Scobie, Eur. J. Org. Chem.,
2013, 26, 5879, DOI: 10.1002/ejoc.200.
Yield: 107 mg (93% yield, white powder), m.p. (EtOH)
91–193 1C.
1
1
H NMR (400 MHz, DMSO-d
6
) d (ppm): 8.33 (br s, 1H), 7.61
(
d, 1H, J = 7.5 Hz), 7.52–7.50 (m, 1H), 7.46 (s, 1H), 7.26 (t, 1H,
J = 7.5 Hz), 7.20 (d, 1H, J = 4.5 Hz), 7.12 (br s, 1H), 6.77 (d, 1H,
J = 7.5 Hz), 6.69 (t, 1H, J = 7.5 Hz), 5.79 (s, 1H).
1
3
C NMR (100 MHz, DMSO-d ) d (ppm): 163.4, 147.7, 143.7,
6
1
33.2, 127.3, 126.7, 126.3, 123.0, 117.1, 115.0, 114.5, 62.5.
LCMS [M + H] m/z 231.
13 B. A. Dar, A. K. Sahu, P. Patidar, J. Patial, P. Sharma,
+
M. Sharma and B. Singh, Am. J. Chem., 2012, 2, 248.
1
4 M. Sharma, S. Pandey, K. Chauhan, D. Sharma, B. Kumar
and P. M. S. Chauhan, J. Org. Chem., 2012, 77, 929.
2-(Thiazol-2-yl)-2,3-dihydroquinazolin-4(1H)-one (3m)
Yield: 109 mg (94% yield, white powder), m.p. (EtOH) 206–207 1C. 15 M.-J. Hour, L.-J. Huang, S.-C. Kuo, Y. Xia, K. Bastow,
1
H NMR (400 MHz, DMSO-d
6
) d (ppm): 8.73 (br s, 1H), 7.77
Y. Nakanishi, E. Hamel and K.-H. Lee, J. Med. Chem.,
2000, 43, 4479.
(
d, 1H, J = 2.8 Hz), 7.64–7.61 (m, 2H), 7.56 (br s, 1H), 7.28 (t, 1H,
J = 7.3 Hz), 6.78 (d, 1H, J = 7.3 Hz), 6.72 (t, 1H, J = 7.3 Hz), 5.98 16 R. A. Bunce and B. Nammalwar, J. Heterocycl. Chem., 2011,
(
s, 1H).
48, 991.
1
3
C NMR (100 MHz, DMSO-d ) d (ppm): 172.6, 162.6, 146.4, 17 M. Wang, J. Gao, Z. Song and L. Wanga, J. Heterocycl. Chem.,
6
1
42.4, 133.5, 127.3, 120.8, 117.7, 114.9, 114.8, 63.7.
LCMS [M + H] m/z 232.
2012, 49, 1250.
+
18 Z. Karimi-Jaberi and L. Zarei, J. Chem. Res., 2012, 36, 194.
This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem., 2013, 37, 3595--3597 3597